JP6462592B2 - Thin-film vascular stent for arterial disease - Google Patents

Description

(Cross-reference of related applications)
[0001] This application claims priority to US Provisional Patent Application No. 61 / 769,042, filed February 25, 2013. This application also claims priority to US Provisional Patent Application No. 61 / 158,200 filed March 6, 2009 and US Provisional Patent Application No. 61 / 158,221 filed March 6, 2009. Related to International Patent Application No. PCT / US2010 / 026430 filed on March 5, 2010. All of the above applications are incorporated herein by reference in their entirety.

(Statement on Federally Sponsored Research or Development)
[0002] This invention was made with government support under Grant No. HL099445 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0003] The present invention relates generally to implantable devices, and more particularly to implantable medical devices for treating peripheral arterial disease (PAD) and surface treatments thereof.

[0004] Lower limb peripheral arterial disease (PAD) is characterized by the accumulation of atherosclerotic plaque in the arteries of the legs. PAD generally exhibits intermittent claudication that can limit lifestyle, but it manifests as chronic or acute limb ischemia and may eventually require amputation. The prevalence of symptomatic PAD increases with age and can be as high as 8% in the population over 70 years. In 2008, approximately 1 million PAD endovascular operations were performed in the United States, a five-fold increase over 10 years ago, representing approximately 70% of total PAD interventions. With the aging of the population, endovascular surgery to treat PAD is increasing and it is estimated that 2 million operations will be performed annually by 2020. Unfortunately, current endovascular treatment is often accompanied by a poor prognosis, and aging populations need to consider new endovascular devices.

[0005] One intravascular device for treating PAD is Gore's Viabahn internal prosthesis. This device uses a self-expanding nitinol stent backbone lined with an expandable polytetrafluoroethylene (ePTFE) liner that is approximately 150 μm thick. The data for this device shows that the 1-year primary patency rate for superficial femoral artery disease is between 65% and 85%. In order to understand the relatively high failure rate of this device, the researchers identified three important issues. These problems are as follows. First, stenosis tends to occur at the proximal and distal ends of the device. Second, the patency rate is not related to the length of injury treated. Third, a significant percentage of patients (about 40% after 5 years) experience late thrombosis.

[0006] Many of the blood vessels that experience PAD are relatively small, having a diameter of only a few millimeters. Thus, relatively thick (about 150 μm) ePTFE is quite thick for the lumen of such blood vessels. As a result, vessel lumen diameter is limited to 300 microns, causing or exacerbating proximal and distal restenosis. The impermeability of ePTFE lining is also a problem. Since ePTFE is a thick polymer, it becomes an impervious obstacle to cell growth and migration. FIG. 1 shows an image taken in a sheep stented iliac artery 3 months after stent insertion. Only two struts 10 of the stent 5 are shown next to the iliac lining 12 because the image is magnified. The ePTFE stent liner 12 is on the luminal side of the strut 10. Thus, the strut 10 is on the abluminal side with respect to the ePTFE stent liner 12. Because the ePTFE stent liner 12 is impermeable, cell-to-cell communication between the luminal endothelial layer on the luminal surface 14 of the ePTFE stent liner 12 and the arterial wall 15 is not possible. Thus, the luminal surface 14 is chronically exposed and acellular. Thus, since the luminal surface 14 cannot be endothelialized, the risk of thrombus is greatly increased. In contrast, neointimal 11 has grown around strut 10. A great deal of evidence suggests that intercellular communication between the luminal endothelial monolayer and the underlying vessel wall leads to excessive smooth muscle cells leading to neointimal hyperplasia (NIH) and eventual stenosis. It is important to prevent proliferation. The impermeability of the ePTFE stent liner 12 prevents the neointima 11 from entering the lumen of the blood vessel, but it is undesirable for the neointima 11 to grow on the struts 10, increasing the probability of restenosis To do. A relatively thick and impermeable ePTFE barrier prevents smooth muscle cell proliferation (ie, an advantageous attribute) while exchanging nutrients between the intima and media, an important feature of normal vascular physiology And also prevents paracrine transmission. Thus, a thick and impermeable coating of ePTFE is a poor option for intravascular devices whose goal is to establish non-pathological vascular homeostasis as quickly and efficiently as possible.

[0007] Accordingly, there is a need in the art for improved techniques and devices for the prevention of restenosis and thrombus in stented blood vessels.

[0008] Provided is a stent cover that promotes healthy luminal endothelium lining while preventing smooth muscle cell migration and consequent neointimal hyperplasia. The stent cover has a micropatterned thin film Nitinol (MTFN) that forms a cylinder to surround and cover the struts or truss members of the stent. The micropattern is large enough to allow sufficient intercellular communication but still has multiple fenestrations in thin film nitinol that are small enough to prevent neointimal hyperplasia. The stent cover extends in a longitudinal dimension from the proximal end to the distal end. There is a corresponding longitudinal dimension or range across each fenestration. In that regard, blood flow in a stented blood vessel generally flows in the longitudinal dimension. Similarly, there is a lateral dimension or range that is orthogonal to the longitudinal dimension across each fenestration. These dimensions exist regardless of whether each fenestration has a similar polygon or is otherwise irregular. Regardless of the fenestration geometry, the lateral and longitudinal dimensions of each fenestration do not exceed the critical dimension to prevent neointimal hyperplasia. This maximum or critical dimension is comparable to that of smooth muscle cells. In one embodiment, the maximum dimension is 10 microns. More generally, the maximum dimension is a dimension that prevents or at least substantially inhibits smooth muscle cell migration through the fenestration, such as 25 microns or less.

[0009] Micropatterned thin film stent covers are very advantageous compared to conventional ePTFE barriers. For example, the fenestration promotes endothelialization on the luminal surface of the stent cover. In contrast to conventional ePTFE barriers that do not undergo such endothelialization, micropatterned thin film stent covers thus prevent thrombus. Although the fenestration can endothelize the luminal surface and thus prevent thrombus, the fenestration also prevents neointimal hyperplasia on the luminal surface of the stent cover. This is because the size of the fenestration is too small for smooth muscle cells to migrate through the fenestration. Also, the resulting cellular information transfer between the endothelial lining on the luminal surface of the stent cover and the vessel wall adjacent to the antiluminal surface of the stent cover may cause hyperplasia of the antiluminal surface of the stent cover. It is thought to prevent. In contrast, neointimal proliferation on the antiluminal surface of a conventional ePTFE barrier (neointima 11 in FIG. 1) is clearly undesirable. Furthermore, the micropatterned thin film stent cover is significantly thinner than conventional ePTFE barriers, thus preventing restenosis resulting from flow contraction. These and other advantages of the advantageous micropatterned thin film stent cover disclosed herein can be further understood from the following non-limiting modes for carrying out the invention.

[0010] The invention will be more fully understood with reference to the following drawings, which are for illustrative purposes only.

[0011] FIG. 3 shows an image taken of a stent with ePTFE cover 3 months later in an iliac artery of a sheep. [0012] FIG. 3 shows an assembly drawing of a PAD stent according to the present invention. [0013] FIG. 2 shows an exploded view of the PAD stent of FIG. [0014] FIG. 6 shows a schematic of an implanted stent with an MTFN cover of the present invention and its effect on “edge effect” stenosis. [0015] FIG. 2 shows a schematic of an implanted stent with an ePTFE cover and its effect on “edge effect” stenosis. [0016] FIG. 6 shows a schematic representation of the effect on migration of implanted stents and SMCs (smooth muscle cells) with MTFN covers of the present invention. [0017] FIG. 2 shows a schematic representation of an implanted stent with an MTFN cover of the present invention and the resulting endothelial monolayer. [0018] Figure 5 is a graph showing the effect of processing time on the wetting angle of an MTFN film of the present invention. [0019] Shown are SEM images of four MTFN sheets, each having a different micropattern of fenestrations according to the present invention. [0020] FIG. 8A shows an optical microscope image of two films with rhombus patterned fenestrations measuring 7.5 μm × 10 μm. [0020] FIG. 8B shows an optical microscope image of two films with rhombus patterned fenestrations measuring 45 μm × 60 μm. [0021] FIGS. 9A-9C show a molecular analysis of blood compatibility of TFN compared to ePTFE, and FIG. 9A shows total thrombus. [0021] FIGS. 9A-9C show a molecular analysis of blood compatibility of TFN compared to ePTFE, and FIG. 9B shows the amount of fibrin and platelet deposits. [0021] FIG. 9C shows a molecular analysis of the blood compatibility of TFN compared to ePTFE, and FIG. 9C shows the amount of fibrin and platelets deposited. [0022] FIG. 10A shows in vitro surface hydration effect and endothelial monolayer image after 1 week at 0 ° contact angle. [0022] FIG. 10B shows the in vitro surface hydration effect and endothelial monolayer image after 1 week at a contact angle of 40 °. [0022] FIG. 10C shows the effect of in vitro surface hydration and endothelial monolayer image after 1 week at a contact angle of 65 °. [0023] FIG. 8B shows a representative image of a vessel wall treated with the stent of FIG. 8A with 7.5 μm × 10 μm perforations. [0024] FIG. 8D shows the contralateral iliac artery treated with the stent cover of FIG. 8B with 45 μm × 60 μm perforations. [0025] FIG. 6 shows a graph of neointimal area for various fenestration sizes. [0026] FIG. 14A shows, at low magnification, an image of an arterial wall treated with a 45 μm × 60 μm stent cover. [0026] FIG. 14B shows an image of an arterial wall treated with a 45 μm × 60 μm stent cover at medium magnification. [0026] FIG. 14C shows a high magnification image of the wall of the artery treated with a 45 μm × 60 μm stent cover. [0027] Shows images of HAEC grown on unpatterned TFN. [0028] Shows HAEC grown on MTFN with a lattice pattern, scale bar is 100 μm. [0028] Shows HAEC grown on MTFN with a lattice pattern, scale bar is 50 μm.

[0029] Referring to the drawings in more detail, for purposes of illustration, the present invention is generally implemented with the apparatus shown in FIGS. It is understood that the apparatus may vary in configuration and part details, and the method may vary in specific steps and order without departing from the basic concepts as disclosed herein. Is done.

[0030] FIGS. 2A and 2B show an assembled view and an exploded view (respectively) of a PAD stent 20 according to the present invention. The stent 20 generally has a micropatterned thin film Nitinol (MTFN) cover 22 disposed around a foldable truss 24. As shown in FIG. 2B, truss 24 may have a plurality of corrugated wire sections or stent struts 28 at anchoring points 26 that allow truss 24 to be compressed to a delivery location in a folded configuration (not shown). Join. In one embodiment, struts 28 can have nitinol. The MTFN sheet 22 generally forms a tubular structure with a very low profile (eg, 5 μm thick) around the truss 24 and has a plurality of perforations as shown in more detail in FIGS.

[0031] Referring to FIGS. 3A-5, it will be appreciated that the MTFN stent cover 22 has several advantages. For example, FIG. 3A shows the portion of the MTFN stent cover 22 that is in contact with the vessel wall 21. For illustrative clarity, the luminal stent struts of the MTFN stent cover 22 are not shown in FIG. 3A. Since the stent cover 22 contains the thin film nitinol, it becomes a barrier having no influence on the blood flow direction as indicated by the arrow F. This does not restrict flow, thus preventing restenosis of the stented blood vessel. In contrast, the conventional ePTFE stent liner 12 as shown in FIG. 3B is much thicker and therefore a much greater obstacle to blood flow as shown by the flow separation zone F _s . The MTFN stent cover 22 also promotes endothelialization 30 of its luminal surface 23 to prevent thrombus, whereas the luminal surface 14 of the conventional ePTFE stent liner 12 is acellular and thus promotes thrombus. To do.

[0032] An exemplary fenestration 40 of the MTFN stent cover 22 is illustrated in FIG. The longitudinal and lateral dimensions of the fenestration 40 are such that the smooth muscle cells 32 within the stented vessel wall pass through the fenestration 40 (ie, from the antiluminal surface 42 of the MTFN stent cover 22 to the lumen). Small enough to prevent migration) (to side surface 44). For example, this dimension of one embodiment does not exceed 10 microns with an accuracy of 1 micron. Therefore, the endothelial cells 34 on the luminal surface 44 do not invade the smooth muscle cells 32, thus preventing neointimal hyperplasia, while still allowing cell-to-cell communication through the thickness of the graft.

[0033] The MTFN stent cover disclosed herein can also include a surface treatment that improves hydrophilicity. The improvement in hydrophilicity is illustrated symbolically by the dotted line 51 in FIG. As a result, the stent surface, such as the luminal surface 44, is chemically modified to facilitate the growth of the robust endothelial monolayer 34.

[0034] The MTFN stent cover 22 is processed to specific dimensions and compositions to facilitate adaptation within the patient's body. Nitinol, ie nickel titanium, is a shape memory alloy of equiatomic (1 Ni atom, 1 Ti atom), generally used for intravascular devices in the form of bulk Nitinol (thickness: over 100 microns) Is done. The MTFN stent cover 22 of the present invention has a thin film nitinol (TFN) manufactured in a sheet shape having a thickness of about 5 μm by sputtering film deposition which has only recently been put to practical use.

[0035] In one embodiment, the MTFN stent cover 22 is produced using a "high temperature target" sputter deposition process detailed in International Patent Application No. PCT / US2010 / 026430 (the '430 application). This can consistently produce thin film nitinol (TFN) with an atomic composition variation of less than 0.5%. In addition to high purity, TFN produced by this method is extremely smooth (surface roughness 5 nm) and more powerful (tensile strength 500 MPa).

[0036] As discussed in the '430 application, the semiconductor substrate can be patterned using a deep reactive ion etching (DRIE) process to produce a patterned substrate. Next, Nitinol is sputtered onto the patterned substrate. The bottom of the etched groove of the substrate also receives a sputtered Nitinol layer, but these areas are separated from the Nitinol deposited on the non-grooved portion of the patterned substrate by vertical groove walls generated by the DRIE process. The Next, when the Nitinol film is peeled from the patterned substrate, the Nitinol film has a fenestration corresponding to the location where the groove is generated in the patterned substrate. As described in further detail in the '430 application, the use of DRIE patterned substrates is extremely advantageous because of the relatively tight tolerances. For example, the shape of the groove (and hence the patterned thin-film nitinol fenestration) can have a tolerance of 1 micron or less. In contrast, wet etching techniques typically have much coarser tolerances. Since the fenestration disclosed herein is relatively small (eg, having longitudinal and transverse dimensions of 10 microns or less), it is advantageous to employ the DRIE process discussed in the '430 application. However, it will be appreciated that in alternative embodiments, nitinol can be sputtered onto a non-patterned substrate so as to later form the fenestration using conventional wet etching techniques.

[0037] Since the patterned substrate is typically planar, the DRIE process discussed in the '430 application typically produces a planar thin film nitinol sheet. In contrast, the stent cover 22 is cylindrical. To form such a three-dimensional structure from a Nitinol sheet, the longitudinal edges of the sheet are sealed together along the seam 23 as shown in FIG. 2B. Accordingly, the length of the stent cover (the longitudinal extent of the stent cover) is the longitudinal length of the initial thin film Nitinol sheet that is subsequently sealed along the longitudinal edges to form the seam 23. It is recognized that it depends on Conversely, the initial thin film Nitinol sheet will have some lateral length along its proximal and distal edges. It is this lateral length of the original thin film Nitinol sheet that determines the diameter of the stent cover lumen. Alternatively, nitinol can be sputtered onto a patterned tubular mandrel and then peeled from the mandrel to produce the stent cover 22. In such an embodiment, the intermediate step of forming a planar sheet and then sealing the sheet to a tubular structure is eliminated. To distinguish the sealed stent cover from the first thin film sheet, the term “MTFN sheet 22” refers to the first planar thin film sheet, and “MTFN stent cover 22” refers to the thin film sheet along the seam 23. It refers to the stent cover that is the result of sealing. In yet an additional alternative embodiment, nitinol can be sputtered onto a planar patterned substrate. Next, a sacrificial layer, such as a chromium layer, is deposited along the sputtered Nitinol swath, and then additional Nitinol is sputtered onto this sacrificial layer and the first deposited Nitinol outside the area covered by the sacrificial layer. be able to. A “layer cake” -like Nitinol sheet also results in a sheet with sealed edges (Nitinol deposited on Nitinol) and a Nitinol layer separated by a sacrificial layer. This sacrificial layer is exposed to the fenestration of the Nitinol layer and can therefore be removed by etching. A three-dimensional (ie, tubular) structure results in a structure that does not need to be sealed along a longitudinal edge, despite the use of a planar substrate. Additional details regarding the manufacture of such tubular thin film nitinol structures can be found in US Pat. No. 6,790,298, the contents of which are hereby incorporated by reference in their entirety.

[0038] The MTFN stent cover 22 of the present disclosure generally has a thickness of less than 50 microns and preferably has a thickness in the range of about 0.1 microns to about 30 microns. Preferably, the thin film ranges from about 0.1, 1, 2, 4, 5, 10, 15, 20, 25, 30 or 50 microns to about 4, 5, 10, 15, 20, 25, or 30 microns. Can have a thickness of More preferably, the thin film can have a thickness of about 4 microns to about 12 microns.

[0039] As a result of being relatively thin, covering the stent truss 24 (FIG. 2B) with the thin shape memory alloy film of the present disclosure results in a minimal and minor increase in the overall device size. For example, since MTFN can be made of a thin film with a thickness of about 5 to about 8 μm, covering the stent with MTFN only increases the device's bulk. Stent struts can have a thickness in the range of, for example, about 2 μm, 4 μm, 6 μm, 7 μm, 10 μm, 17 μm, 18 μm, or 20 μm.

[0040] Both the truss 24 and the MTFN stent cover 22 can be produced in a range of shapes and sizes. For example, a thin film of shape memory alloy can be made square or rectangular, for example, when laid flat, the sheet can have a rectangular appearance with a longer longitudinal dimension and a shorter lateral dimension. . Such square or rectangular dimensions can be selected from a wide range.

[0041] In some embodiments, the width (lateral dimension) of such a square or rectangle is, for example, about 0.5 mm, 1 mm, 3 mm, 5 mm, 10 mm, 16 mm, 20 mm, 25 mm, 30 mm, or 40 mm. It can be a range. The width is generally a function of the inner diameter of the lumen being treated.

[0042] Accordingly, the length (longitudinal dimension) of such a square or rectangle may be in the range of, for example, about 0.5 mm, 2 mm, 5 mm, 15 mm, 20 mm, mm, 50 mm, or 100 mm. . In general, the length is a function of the size of the area to be treated.

[0043] Adjacent sides of the sheet 22 need not be perpendicular. The sheet 22 can have a configuration that is not an infinite loop, for example, the sheet can have two distal edges as the end of the sheet and can be separated in length dimension.

[0044] The thin film of the shape memory alloy can be formed in a wide variety of shapes other than a square or a rectangle. For example, shape memory alloy thin films can be made to resemble other polygons, circles, ellipses, crescents, or any shape.

[0045] In one embodiment, the sheet 22 comprises a generally rectangular thin film sheet that is wound into a generally tubular shape having a longitudinal direction and a radial direction. The two distal edges of the sheet define two ends of a tubular shape and touch or overlap.

[0046] In another embodiment, the sheet has a compact form having a first inner diameter, and the first inner diameter such that the sheet contacts the lumen wall with a radius equal to or slightly greater than the radius of the lumen. Having a deployed configuration with a larger second inner diameter.

[0047] Another advantage of the MTFN sheet 22 of the present invention is that its surface properties can be controlled by chemical treatment. In a preferred embodiment, the MTFN sheet 22 is treated according to the method disclosed in the '430 application, which removes the original surface oxide layer of the film with a buffered oxide etchant followed by nitric acid (HNO ₃ ), And soaked in hydrogen peroxide (H ₂ O ₂ ). This process can generate a TiO layer (eg, 100 nm thick) and deposit charged hydroxyl groups on the surface, as confirmed by high resolution transmission electron microscopy (HRTEM). The negative charge mimics the negative charge of the vascular endothelium and can be manipulated to promote rapid endothelialization (see FIGS. 10A-10C, described in further detail below).

[0048] One tool that characterizes the hydrophilicity of the surface 44 of the MTFN sheet 22 is the wetting angle. FIG. 6 shows the effect of processing time on the wetting angle of the sheet 22. Extremely, untreated TFN has a wet contact angle of 65 °, and sheet 22 treated in H ₂ O ₂ for 15 hours has a contact angle of 0 ° (ie, a superhydrophilic surface). This treatment changes the surface properties (ie, negative charge and TiO layer) to achieve a contact angle in the range of 0 ° to 65 °, which can be used to alter the properties of the stent 20. it can.

[0049] Another important advantage of the MTFN stent cover 22 is that the permeability (ie, porosity) and geometry can be precisely controlled. As previously discussed, using the deep reactive ion etching (DRIE) method disclosed in the '430 application to produce relatively small fenestrations with high accuracy (1 micron tolerance). Can do. Thus, fenestrations can be achieved that prevent smooth muscle migration through the fenestration and have a maximum dimension of, for example, 25 microns or less, or even 10 microns or less.

[0050] An example of four different MTFN sheets produced is illustrated in FIG. 7 and is a variety that can be sized to prevent smooth muscle migration but still allow fluid exchange to promote endothelialization. Various shapes of fenestrations are shown. For example, the sheet 50 can have a plurality of elliptical slots 52, the sheet 60 can have a pattern of circular holes 62, and the sheet 70 is thin to separate the fenestrations in a “chain link fence” fashion. The rhombus-shaped boundary 72 can be provided, and the sheet 80 can have a plurality of rhombus-shaped fenestrations 82.

[0051] The fenestrations can be aligned with an accurate regular array (ie, a resolution of 2 microns or less). This is a unique advantage of the MTFN sheet 22 over ePTFE and other biomaterials. For example, FIG. 8A shows a rhombus-shaped fenestration in which the longitudinal dimension of each fenestration 92 is 10 microns and the lateral dimension of each fenestration 92 is 7.5 microns (7.5 μm × 10 μm). 2 is an optical microscope image of a sheet 90 having 92. Similarly, FIG. 8B is an optical microscope image of a sheet 94 having a rhombus-shaped opening portion 96 having a size of 45 μm × 60 μm. These patterns were used in preliminary stent cover experiments discussed below. Each fenestration 92 is smaller than the smooth muscle cell (SMC) 32 (see FIG. 4) so that the sheet 90 prevents SMC from migrating to the stent luminal surface and the resulting NIH, but is still open. It can act as a filter that allows the exchange of nutrients and intercellular signaling molecules through the window 92. The size of such openings allows biological interaction and achieves improved results.

[0052] In the following discussion, performed with MTFN22 of the present invention, the wet contact angle of TFN is experimentally correlated with its blood compatibility and in vitro endothelial cell proliferation, as well as its ability to support neointimal proliferation in vivo. The test will be described in detail. To demonstrate the blood compatibility of the MTFN-based stent of the present invention, a series of experiments was performed. The original stent was fabricated using TFN with a polar contact angle of 65 ° or 0 ° and no micropattern. The resulting device, along with ePTFE controls, was deployed in a custom made in vitro model that circulates fresh whole blood that mimics moderate arterial stenosis. After testing, the three materials were qualitatively analyzed with a scanning electron microscope (SEM) and quantitatively analyzed with a series of molecular assays.

[0053] FIGS. 9A-9C are graphs of results obtained from molecular analysis of blood compatibility of TFN compared to ePTFE. In particular, FIG. 9A shows the total thrombus deposits for the ePTFE control and two TFN examples, and FIGS. 9B and 9C show the fibrin and platelet deposits for these devices, respectively. The study was placed in a whole blood circulation model with a wall shear rate that mimics moderate arterial stenosis for 3 hours.

[0054] Both 0 ° and 65 ° TFN devices had significantly less blood product compared to adherence to the control ePTFE device. In the case of platelets (FIG. 9C), the original ePTFE stent was more than two orders of magnitude more than the original TFN device. Scanning electron microscopy (SEM) and mass spectrometry data confirmed all of these findings. In SEM, the ePTFE device was almost completely hidden by the thrombus, but both types of TFN could be clearly seen with sparse fibrin, platelet, and red blood cell coverage. Similarly, the trends measured in FIGS. 9A to 9C were confirmed by mass spectrometry. For example, mass spectrometry has demonstrated that the ePTFE device has about 10 times the amount of hemoglobin α chain and β chain attached to any TFN device. This data strongly suggests that the blood compatibility of TFN is significantly improved compared to ePTFE and that the contact angle has a significant impact on blood interaction. Based on these results, the MTFN stent 20 of the present disclosure is believed to reduce the incidence of both acute and late thrombi as compared to the equivalent of ePTFE.

[0055] Also, the surface hydration properties of MTFN were examined for effects on endothelial proliferation and neointimal structure. A major measure of the success of an indwelling intravascular device is the ability to rapidly and fully endothelialize while minimizing the amount of neointimal proliferation. As discussed with respect to FIG. 1, this is an important limitation of stents covered with ePTFE. To evaluate the correlation between contact angle and endothelialization, TFN with three different contact angles (0 °, 40 °, and 65 °) was tested. In particular, Human Aortic Endothelial Cells (Human Aortic Endothelial Cells (HAEC), Lonza, Switzerland) were cultured with TFN samples for 1, 3, and 7 days. After each test time, the samples were stained with AlexaFluor 488 phalloidin (F actin specific) and DAPI (nuclei).

[0056] The effects of surface hydration in vitro after 1 week and representative images of the endothelial monolayer are shown in FIGS. 10A-10C (N = 3, p <0.05). These results indicate that a TFN with a contact angle of 40 ° helps a more confluent and faster proliferating endothelial monolayer than a 65 ° or 0 ° membrane.

[0057] In vivo data was also obtained showing the effect of contact angle on the healing response after placement of an intravascular device. For this test, two TFN covered stents with a contact angle of 0 ° or 65 ° and no micropattern were fabricated and placed in the porcine iliac artery. After 30 days, the device was recovered and sliced for pathological examination. The 0 ° sample demonstrated that there is a neointimal that is thinner and less organized and less inflammatory infiltrated compared to the 65 ° device. This data correlates well with the in vitro results and shows that the 0 ° thin film has more endothelial growth compared to the 65 ° membrane.

[0058] Accordingly, the MTFN sheet 22 is subjected to processing time (eg, hydrogen peroxide (H) to assist rapid proliferation of functional endothelial monolayers on the MTFN device 20 according to an optimal contact angle (eg, 40 ° or less). ₂ O ₂ ) can be fabricated by creating a surface (see FIG. 9A) that minimizes thrombus adhesion while controlling the processing time in the bath (see FIG. 6)).

[0059] The micropattern pore size was also examined for neointimal thickness and antiluminal SMC migration. Preliminary studies were performed to examine the effect of MTFN perforation size (ie permeability) on SMC migration and neointimal proliferation in vivo. Three types of MTFN sheets were used for this study. Each sheet had a rhombus shaped opening having dimensions of 7.5 × 10 μm (sheet 90 in FIG. 8A), 10 × 20 μm, and 45 × 60 μm (sheet 94 in FIG. 8B). The MTFN-covered stent was then placed in the porcine iliac artery and harvested 30 days later.

[0060] FIG. 11 shows a representative image of a vessel wall 100 treated with an MTFN stent cover 90 having 7.5 μm × 10 μm perforations (FIG. 8A). The neointima 102 is thin, well organized, and does not extend beyond the level of the stent strut 28 and into the vascular lumen 108. FIG. 12 shows the same animal contralateral iliac artery 104 treated with the stent cover 94 of FIG. 8B with 45 μm × 60 μm perforations at the same magnification. The neointimal 106 was thick and unorganized, increasing the number of inflammatory cells.

[0061] For quantitative comparison, FIG. 13 shows neointimal area (NIA−) for various fenestration sizes ranging from 7.5 × 10 micron fenestration to 45 × 60 micron fenestration. 2 shows a graph (defined as the area between the MTFN stent cover and the open vessel lumen 108). FIG. 13 shows that NIA increases with increasing MTFN fenestration size. 7.5 [mu] m × 10 [mu] m of NIA device (6.0 ± 0.7 mm ²⁾ is 3 months after 11.9 ± 4.3 mm ² ePTFE covered stent showing the NIA that the implanted in sheep (not shown) Note that it is much smaller than NIA. The right end of FIG. 13 includes NIA measurements for two films without micropatterns with contact angles of 0 ° and 65 ° (N = 1 for unpatterned devices). These results demonstrate that NIA increases without fenestrations regardless of contact angle (ie, as with a relatively impermeable ePTFE device), which is quick and well organized It appears that there is no cell-to-cell communication between the layers of the vessel wall for the cured healing response.

[0062] This study shows that SMC32 migrates across the MTFN barrier in devices with large fenestrations (eg 45 μm × 60 μm) but not in devices with small fenestrations (eg 7.5 μm × 10 μm) This proved to be obvious. FIGS. 14A-14C show the walls of an artery treated with a 45 μm × 60 μm device at low, medium and high magnification, respectively. The fenestration can be seen as a small break in the MTFN stent cover. Strong smooth muscle cell migration is observed at the fenestration site (there is a black arrow mark, most clearly in FIGS. 14B and 14C). These areas of cell migration look like “small volcanoes” and massive SMC migration from the antiluminal side of the MTFN stent cover is observed.

[0063] These images provide “critical dimension” evidence that the SMC migration across the MTFN is blocked while the intercellular signaling pathway is still working. Therefore, it is ideal that the vertical and horizontal dimensions of the fenestration part are less than 10 μm, and preferably 5 μm to 10 μm. More generally, these dimensions should be less than 25 microns and more generally less than or equal to dimensions that prevent smooth muscle migration.

[0064] Based on these, in vivo, MTFN covered stents with fenestrations designed with “critical dimensions” (eg, less than 10 μm, ideally about 5 μm to about 10 μm), while reducing NIH, An information transmission path is provided between the luminal endothelial layer and the underlying blood vessel wall in a manner not possible with an ePTFE-based device.

[0065] The effect of micropattern geometry on endothelial proliferation was also examined. For these studies, human aortic endothelial cells (HAEC) were grown on various geometric shapes of MTFN and grown for 3 days. Samples were stained with DAPI and phalloidin and imaged with a fluorescence microscope. FIG. 15A shows HAEC grown on unpatterned TFN. The rounded “cobblestone” morphology is typical of ECs grown under normal culture conditions. FIG. 15B (scale bar is 100 μm) and FIG. 15C (scale bar is 50 μm) show HAEC grown on MTFN with a lattice pattern (similar to MTFN sheet 70 of FIG. 7). The lower left inset shows the hole geometry used. The cells adopt an elongate form that follows the geometric design of MTFN, indicating that the micropattern geometry adjusts the endothelium form (e.g., elongate and / or multifaceted geometry with straight edges is preferred) ). Of note, these results were obtained using TFN with a contact angle of 65 °, which is less confluent in HAEC growth when the data presented in the previous section. Explain why. That is, a wetting angle of 40 ° appears to be optimal. Nevertheless, these findings are critical when considering the relationship between endothelial morphology and function. It is well established that vascular areas prone to atherosclerosis (such as bifurcations) are exposed to low vibration shear stress. The ECs in these regions employ a round “boulder” morphology, increasing the expression of immunoregulatory surface receptors. Conversely, the “atherogenesis inhibition” region is usually straight and exposed to high unidirectional shear stress. The ECs seen here employ an elongated “spindle” configuration with reduced expression of non-inflammatory surface receptors. Based on these discoveries, the appropriately patterned MTFN stent 20 of the present invention can serve as a scaffold to promote atherogenesis-inhibited EC morphology in ways that are not possible with ePTFE-based stents.

[0066] The MTFN-based stent of the present invention addresses the following two main problems associated with ePTFE covered stents. That is: 1. patency independent of the length of the treated lesion, and Late graft thrombus. Based on the above findings, the thickness of ePTFE causes a size mismatch with the blood vessel wall, leading to restenosis, and the ePTFE barrier is relatively impermeable. It is thought that information transmission with the wall is prevented. This causes the endothelialization of the ePTFE graft to fail, producing a chronically exposed thrombogenic surface that predisposes late thrombi to the patient.

[0067] The MTFN-based stent of the present invention overcomes these limitations in at least three ways. First, the MTFN stent 20 of the present invention has a very low profile, thereby eliminating edge effect stenosis and persistent flow separation zones by allowing proximal and distal cell migration. Secondly, the MTFN stent 20 of the present invention controls the transluminal communication between the neointima and the vessel wall over the entire length of the stent, while preventing migration of the antiluminal SMC. It can be porous. Third, the MTFN stent 20 of the present invention is non-thrombogenic, non-immunogenic on the luminal surface of the stent that is in direct communication with the underlying vessel wall to maintain long-term patency. Has surface properties and fenestration geometry that can be optimized to promote cortical growth.

[0068] Although the foregoing description includes many details, this is not to be construed as limiting the scope of the invention and merely providing some illustrations of the presently preferred embodiments of the invention. I want to be. Accordingly, the scope of the present invention encompasses all other embodiments that will be apparent to those skilled in the art, and thus the scope of the present invention is not limited to anything other than the claims, and is explicitly set forth herein. Unless stated, the singular element is not intended to mean “one and only one”, but is understood to mean “one or more”. All structural, chemical, and functional equivalents of elements known to those skilled in the art of the preferred embodiments described above are expressly incorporated herein by reference and are encompassed by the claims. Shall. Further, as encompassed by the claims, the device or method need not address each problem sought to be solved by the present invention. Furthermore, no element, component or method step of this disclosure shall be publicly disclosed, regardless of whether that element, component or method step is explicitly recited in the claims. And No element in the claims should be construed in accordance with the paragraph of 35 USC 112, sixth paragraph, unless that element is explicitly recited using the phrase "means."

Claims (23)

An implant for treating peripheral arterial disease,
A plurality of stent struts;
Wherein the plurality of configured to be positioned around the stent struts, and a thin film nitinol (MTFN) scan stent covered fine pattern comprising a plurality of fenestrations,
Including
The fenestration is the migration of smooth muscle cells of the abluminal through the fenestration or less critical dimensions to deter, and is more critical dimensions that enable cell-to-cell communication, implants. The MTFN stent cover extends in a longitudinal dimension, the fenestration has a size having a maximum longitudinal dimension of 10 μm or less, and the fenestration has a size having a lateral maximum dimension of 10 μm or less. The implant of claim 1 , wherein: The implant according to claim 2, wherein the longitudinal and lateral dimensions of the fenestration part are 5 µm to 10 µm. The MTFN stent cover has a thickness of less than 5 0 .mu.m, implant according to claim 1. The implant of claim 4 , wherein the MTFN stent cover has a thickness of less than 10 μm. The implant of claim 5 , wherein the MTFN stent cover has a thickness in the range of 5 μm to 10 μm. The implant of claim 1, wherein the MTFN stent cover has at least one hydrophilic surface having a water contact angle of 40 ° or less. The implant of claim 7 , wherein the MTFN stent cover has at least one hydrophilic surface having a water contact angle of 40 °.   The implant of claim 1, wherein each of the fenestrations has an elongated shape. The implant of claim 9 , wherein the fenestration has a straight edge. The MTFN stent cover is
Including a generally rectangular thin film sheet wound into a generally tubular shape having a longitudinal direction and a radial direction;
Two longitudinal edges of the sheet are at least in contact to form the tubular shape;
The implant of claim 1, wherein the sheet has a compact configuration with a first inner diameter and a deployed configuration having a second inner diameter greater than the first inner diameter. The implant is configured to be delivered into a blood vessel in the compact configuration, the implant is configured to expand into a deployed configuration at a therapeutic location within the blood vessel, and the implant is configured to expand the vessel. It extends to the inner surface, configured to at least contact with the inner surface, the implant according to claim 1 1. The plurality of stent struts are configured to be deployed in a compressed configuration when constrained within a catheter, such that the plurality of stent struts automatically expand at a treatment site if not constrained within the catheter. implant according configured, the MTFN stent cover is configured to expand with expansion of the stent struts, in claim 1 1. A stent for treating peripheral arterial disease,
A tubular truss,
A sheet comprising thin film nickel titanium (NiTi) configured to surround the truss;
Including
The sheet has a compact configuration having a first inner diameter and a deployed configuration having a second inner diameter greater than the first inner diameter;
The stent is configured to be delivered into a blood vessel in the compact configuration;
The stent is configured to expand into a deployed configuration at a treatment location within the blood vessel;
The sheet is configured to expand to and contact the inner surface of a blood vessel, the sheet including a micropattern of fenestrations;
The fenestration is the migration of smooth muscle cells of the abluminal through said sheet or less critical dimensions to deter, and is more critical dimensions that enable cell-to-cell communication through said seat, Stent. The fenestration is a size having a maximum dimension of less than 1 0 .mu.m, stent of claim 1 4. The fenestration is a size having a maximum dimension of 5 Myuemu～10myuemu, stent of claim 1 5. The thin sheet has a thickness of less than 5 0 .mu.m, stent of claim 1 4. The stent according to claim 17 , wherein the thin film sheet has a thickness of less than 10 μm. The thin sheet has a thickness in the range of 5 Myuemu～10myuemu, stent of claim 1 8. The sheet, 4 0 ° with at least one hydrophilic surface has a water contact angle of less The stent of claim 1 4. It said sheet has at least one hydrophilic surface has a water contact angle of 4 0 °, The stent of claim 2 0. The fenestration has an elongated shape, stent of claim 1 4. The fenestration has an edge portion of the straight stent of claim 2 2.

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